YAKUGAI Ombudsperson “Medwatcher Japan”
AM Bldg 4F, Shinjuku 1-14-4, Shinjuku-ku, Tokyo 160-0022, Japan
Mail: yakugai@t3.rim.or.jp
Fax: +81-3-3350-0607

2 November, 2016

Refutation of Global Advisory Committee on Vaccine Safety “Statement on Safetyof HPV Vaccines: 17 December 2015”
I. Overview of the GACVS Statement and the situation in Japan
Human papilloma virus (HPV) vaccines were approved relatively late in Japan
compared with Western countries (October 2009 for Cervarix and July 2011 for
Gardasil). The vaccination rate was low at the beginning; however, after an
HPV-vaccine promotion campaign that led to government subsidization of the cost of
the vaccine in November 2010, the vaccination rate increased exponentially, followedby an unexpected increase in adverse event (AE) reports. Within 3 months of theformal designation as a routine vaccination, the Ministry of Health, Labour and Welfare(MHLW) withdrew its active recommendation on the grounds of “an undeniable causal
relationship between persistent pain and the vaccination”1).
However, in a statement released on December 17, 2015, the World HealthOrganization (WHO) Global Advisory Committee on Vaccine Safety (GACVS)
claimed that it had “not found any safety issue that would alter its recommendations forthe use of the vaccine” and that, “the impact of HPV vaccines on HPV-related clinicaloutcomes, including precancerous lesions is well established”. Direct criticism wasleveled at Japan in the form that, “policy decisions based on weak evidence, leading tolack of use of safe and effective vaccines, can result in real harm”2).
This unwarranted criticism shows not only incorrect understanding of the situation in
Japan regarding AEs following HPV vaccination but mistaken assessment of thevaccine’s risk-benefit balance. It also disregards the fundamentals of healthpolicy-making, namely that appropriate preventive measures should be established byeach individual country taking into account the state of disease prevalence, hygienic
environment, education, and economic status in that country. The main problems arisingfrom the GACVS’s stance are outlined below.

1II. Safety(1) AE reporting in Japan
Table 1 shows the number of serious adverse event (AE)/adverse drug reaction (ADR)
reports, as defined according to the ICH E2A guidelines,3) submitted for HPV vaccines
by the vaccine makers and medical professionals as of the end of February 20164).
These numbers far exceed those for other vaccines5-14) (Figs. 1 and 2). As these data
are compiled from voluntary reports, the actual incidence of AEs may well be far
higher15,16). Countries other than Japan have also indicated major problems with thesafety of HPV vaccines5,17). Ignoring these “inconvenient” facts in an effort to promote
HPV vaccination contradicts the primary responsibility of WHO, which is todispassionately assess risks and benefits.
Table 1: Serious AE/ADR reports of HPV vaccines in Japan4)
Total Doses*

Total Number ofSerious AE/ADR reports

Inoculated Persons*From MAH

From Med. Institut.

Cervarix

6,998,266

2,590,000

835

448

Gardasil

1,924,121

800,000

124

165*Estimated from sales data
AE: adverse event;Observation period:

ADR: adverse drug reaction;

MAH: marketing authorization holder

Cervarix: 2009 Dec～2016 Feb

2Gardasil: 2011 Aug～2016 Feb

Fig. 1: The rate of ADRs from Cervarix compared to other vaccines in the United Kingdom
immunization schedule5,9)Data sourced from the report provided by the United Kingdom Medicines and Healthcare
products Regulatory Agency (MHRA) for the Joint Committee on Vaccination and
Immunisation, June 2010.
MMR: measles, mumps, and rubella.

Cervarix
Gardasil
PrevnarMeasles
BCG
ActHIB
DPT
DPT＆Polio
RubellaMeasles/Rubella
B-encephalitis
Varicella
Inactivated Polio
Diphtheria/Tetanus

0

50

100

150

200

Fig. 2: Severe ADRs from HPV vaccines and other vaccines in Japan 6-8) (ADRs/106 inocul.)
BCG: Bacille Calmette Guerin;

DPT: diphtheria-pertussis-tetanus

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Reported serious AEs include diverse, complex, multi-system symptoms such as
seizures; disturbance of consciousness; systemic pain including headache, myalgia,
arthralgia, back pain and other pain; motor dysfunction such as paralysis, muscular
weakness, exhaustion, and involuntary movements; numbness and sensory disturbance;autonomic symptoms including dizziness, hypotension, tachycardia, nausea, vomiting,and diarrhea; respiratory dysfunction including dyspnea and asthma; endocrine
disorders such as menstrual disorder and hypermenorrhea; hypersensitivity to light andsound; psychological symptoms including anxiety, frustration, hallucinations, andovereating; higher brain dysfunction and cognitive impairments including memory
impairment, disorientation, and loss of concentration; and sleep disorders, hypersomnia
and sudden sleep attacks. In some cases, these symptoms impair learning and result in
extreme fatigue and decreased motivation, negatively impacting everyday life11-14). In
the following sections, these diverse symptoms will be referred to as “post-HPV
vaccination symptoms”.
Many of these symptoms also overlap with complex regional pain syndrome (CRPS),
postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS),and fibromyalgia syndrome (FMS). Thus, patients who present symptoms after HPV
vaccination are labeled with various diagnoses and the medical community has madelittle effort to comprehensively view the symptoms as an overall disease state caused by
vaccination. Patients are placed into the category that best approximates their symptoms
from existing disease concepts and are interpreted simply as “misfits” in whom
symptoms coincidentally happened to appear after vaccination. Patients who ultimately
cannot be given a formal “diagnosis” are treated as if they are having psychogenic
reactions or have a malingering disorder, and such treatment causes patients further
emotional distress. This problem is not limited to Japan, and other countries havereported many patients in similar situations5,17).
Under these circumstances, the WHO and national health authorities should not
immediately rule out a causal relationship with the vaccine. Rather, when faced withsuch a situation, it is their responsibility to collect case reports, including disputablecases; conduct detailed interviews about AEs; and undertake the necessary case-control
and cohort studies based on the emerging clinical data.
(2) Investigation by the MHLW
Regarding Japan, the GACVS statement says that, “review of clinical data by thenational expert committee led to a conclusion that symptoms were not related to thevaccine”; however, there are major problems with the expert committee’s investigation.
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On January 20, 2014, the expert advisory committee established by the MHLW
presented the view that the diverse pain and motor dysfunctions experienced by many
individuals after HPV vaccination comprised psychosomatic reactions to anxiety or
stimulatory pain caused by needle injection and were not due to vaccine components. 18)
However, the members of that committee included very few doctors who haveactually examined patients with post-HPV vaccination symptoms. Furthermore, thecommittee’s investigation focused exclusively on pain and motor dysfunction andignored the many other diverse post-HPV vaccination symptoms that have been
observed. Usually, in a drug regulatory agency, assessors classify and code ADR reports
according to a dictionary such as MedDRA (Medical Dictionary for Regulatory
Activities) or ICD10 (The 10th revision of the International Statistical Classification of
Diseases and Related Health Problems), and look for evidence that the medicine was thecause, which makes it difficult to act based on the actual reports. Detailed descriptions
can tell us much that we do not know and yet need to know, but these descriptions
mostly do not appear in the coded reports. The conference minutes of the expert
advisory committee on the HPV vaccine show that the committee held only a cursory
discussion in which causality was denied18). Cases in which symptoms appeared morethan 1 month after vaccination were excluded from investigation; however, subsequent
study has clarified that symptoms commonly manifest even after a considerable periodof time has elapsed since vaccination11,13). In addition, data published by the French
National Agency for Medicines and Health Products Safety19), which was quoted in the
GACVS statement, also included a much longer surveillance period; specifically, themedian time between final vaccination and onset of Guillain-Barre syndrome wasreported to be 4.6 months with an interquartile range of 0.9-11.3 months.
Consequently, the MHLW itself subsequently extended the observation period.
The methods used for determining psychosomatic reactions to be the cause of
symptoms are also open to question18). The expert advisory committee proposed thefollowing possible causes for post-HPV vaccination symptoms: 1) neurologicaldisorder, 2) intoxication, 3) immunological reaction, and 4) psychosomatic reaction.
For causes 1), 2) and 3), if there were any contradictory findings at all, the possibility
was dismissed. For cause 4), if there were any suggestive symptoms, the cases were
accepted as psychosomatic while contradictory findings were ignored. This approach isarbitrary and thus the conclusion is not warranted based on the methodology.
Support for the expert advisory committee’s conclusion remains far from universal.
Doctors and researchers who have actually examined patients with post-HPV
vaccination symptoms have criticized the conclusion and pointed out that it is difficult5to explain all symptoms as psychosomatic reactions. Furthermore, as 11 of 15
members of the expert advisory committee have direct relationships with vaccine
manufacturers, the public is justified in requesting that a more diverse range ofscientists review the relevant data20). Thus, the safety of the HPV vaccine remains far
from certain in Japan, justifying the public’s strong concerns.
(3) Criticism of the evidence for safety mentioned in the GACVS statement
Regarding the safety of the HPV vaccine, the GACVS statement claimed it had not
found any safety issues that would alter its recommendations for the use of the vaccine
and criticized Japan’s decision to stop actively promoting HPV vaccination. However,the studies19,21-25) cited by the GACVS as evidence for the vaccine’s safety raise thefollowing fundamental questions:i) Genetic basis of autoimmunity
Most autoimmune diseases are complex polygenic conditions in which affectedindividuals inherit multiple genetic polymorphisms that contribute to diseasesusceptibility, and these genes interact with environmental factors to cause the disease.
It is a well-known fact that some Human Leukocyte Antigen (HLA) alleles occur at ahigher frequency in patients with certain autoimmune diseases than in the general
population26).
The alleged primary evidence at present for the safety of the HPV vaccine is that
there is no statistically significant difference in the incidence of autoimmune diseases invaccinated females compared to unvaccinated females or the general population.
However, since the proportion of genetically susceptible people in the general
population is very small and limited, simple comparisons of the incidence ofautoimmune diseases between those who have been vaccinated and a control(unvaccinated) group are likely to show no significant difference. Therefore, argumentsthat do not take this issue into consideration cannot assure the safety of this vaccine.
Many autoimmune diseases have a relatively low baseline prevalence; therefore,
careful, large-scale post-marketing surveillance that bears in mind the immunologicalcharacteristics of individual patients is required to scientifically verify the relationshipbetween vaccination and autoimmune diseases27).
ii) Coding and concealment of “inconvenient” facts
In drug regulatory agencies and the pharmaceutical industry, all AEs in a patient’s
medical record are coded for computer processing and thus details contained in the raw
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data are “lost” which has the effect of masking the clinical significance and extent ofdrug risk28,29). This approach amounts to nothing more than simply isolating andretrospectively analyzing each post-HPV vaccination symptom within the framework ofexisting disease concepts rather than viewing the symptoms comprehensively.
iii) Paradigm shift
HPV is equipped with various immune evasion mechanisms, which could cause theimmune system to become more tolerant to the infection, creating a microenvironment
susceptible to further infection and facilitating progression of cervical intraepithelial
neoplasia (CIN). To counteract these immune evasion mechanisms, the HPV vaccine isdesigned to maintain an extraordinarily-high antibody level for more than a decade30,31),
and this shifts the HPV vaccine out of the paradigm of a “vaccine” as we conventionally
understand it. In light of these unique characteristics of the HPV vaccine, a morethorough evaluation of its safety is essential.
III. Effectiveness
While the GACVS statement claims that, “the impact of HPV vaccines on
HPV-related clinical outcomes, including precancerous lesions is well established”, inactuality, the effectiveness of the HPV vaccine is quite limited, as discussed below.
(1) Limitations of effectivenessFirst, the only verified effect of the HPV vaccine is a preventive effect on
precancerous lesions (specifically CIN); the preventive effect on cervical cancer itself
has not been established. Furthermore, the effects of the vaccines that are currently
approved in Japan (Cervarix and Gardasil) on precancerous lesions have only been
demonstrated for HPV 16 and 18, which according to the most reliable studies represent
only 50% of cervical cancer cases in Japan32).
Furthermore, 10% or less of cases of high-risk HPV infection result in persistentinfection that can cause cancer, while the large majority of any precancerous lesions(CIN) that do develop resolve before becoming cancer 33,34). Therefore, only 0.15% of
individuals infected with high-risk HPV develop (invasive) cancer35,36). Even if cancer
occurs, with regular checkups it can be detected at an early stage and appropriate
treatment (surgery, radiation, and chemotherapy) saves many lives. Based on thesefacts, promoting educational activities emphasizing the importance of screening andearly detection, and providing an environment in which women feel more comfortable
undergoing Pap testing, would be far more effective at preventing cervical cancer, rather
7than pressuring teenage girls to receive the existing HPV vaccination, with all its
problems.
Proponents of these vaccines often state that HPV vaccines are 98-100% effective inpreventing cervical cancer; however, these figures represent the percentage of relativerisk reduction (RRR). RRR can easily lead to misunderstandings and it is sometimes
intentionally misused to exaggerate both benefit and harm37,38). In reality, the absoluterisk reduction (ARR) expected by HPV vaccines is at most 0.1-0.7%. Furthermore, this
only indicates the risk reduction of developing precancerous lesions, while the risk forcervical cancer remains unknown.
(2) Cancer screening as an alternative measure
Promoting cervical cancer screening is another important measure against cervicalcancer. The low screening rate for cervical cancer in Japan compared to Westerncountries has long been pointed out. In particular, young women with no experience ofpregnancy are reluctant to undergo gynecological examinations in Japan. Accessibility
to examinations by female doctors and acceptance of self-sampling would undoubtedly
increase the screening rates. Improving and promoting screening methods in this way
would markedly decrease the cervical cancer mortality rate39).
IV. Conclusion
The proponents of the HPV vaccine often state that only a fraction of individuals who
undergo HPV vaccination will experience AEs and the risks need to be weighed against
the benefit of cancer prevention. However, complaints of AEs and cases of serious andprotracted symptoms are more numerous for the HPV vaccine than for other vaccines.
The situation in Japan is similar to that in other countries, which also report a picture ofa specific cluster of serious and complex symptoms that develop across multiple bodysystems over an extended period of time.
Girls who have previously enjoyed good health are suddenly tormented by pain andworry, and their life dreams and aspirations are put on hold. Symptoms following HPV
vaccination can result in major disadvantages that seriously impair a wide range ofaspects of daily life such as inability to do even simple calculations, severe memory
impairment and learning disabilities, problems with walking, becoming bedridden due
to pain and motor dysfunction, and giving up seeking a higher education. In addition to
the huge social costs, lives and human dignity have been ruined.
Furthermore, treatment for these symptoms has yet to be established and no method
currently exits for identifying individuals likely to be susceptible to serious AEs. The
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mortality rate from cervical cancer in Japan is being maintained at a low levelcomparable to that in Western countries. Therefore, balancing the serious concerns
regarding the safety of the HPV vaccine against its limited effects, there is nocompelling reason for Japan to recommend vaccination. The Japanese government’s
decision to stop actively promoting HPV vaccination in light of the current situation isjustified; the GACVS’s criticism of this decision is not.
Despite not conducting its own investigation into the symptoms following HPV
vaccination, the GACVS is nevertheless criticizing the independent policies of Japan,
one of its member countries, while attempting to compel compliance with specificpolicies using only the force of authority as the basis. This criticism constitutes a failureof the WHO to live up to its responsibility as an international body having the statedgoal of strengthening health systems, and it is a criticism to which we strongly object.
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